An efficient and reusable catalyst based on Pd/CeO2 for the room temperature aerobic Suzuki-Miyaura reaction in water/ethanol

Article abstract of DOI:10.1016/j.molcata.2009.09.012

The Pd/CeO₂ system behaves as an efficient precatalyst for the Suzuki-Miyaura cross-coupling under mild conditions (298 K, in air) in ethanol/water. A broad range of aryl bromides, including those deactivated, and arylboronic acids underwent Suzuki-Miyaura coupling with quantitative GC yields of asymmetric biaryls. Isolated yields and purity of the coupling products were good to excellent. A careful investigation through a series of suitable tests unequivocally showed that the C-C cross-coupling is accomplished via homogeneous mechanism by leached palladium(0). Noticeably, the Pd/CeO₂ system can be recycled at least ten times without loss of activity.

Full text of DOI:10.1016/j.molcata.2009.09.012

Journal of Molecular Catalysis A: Chemical 315 (2010) 197–204
Contents lists available at ScienceDirect
Journal of Molecular Catalysis A: Chemical
journal homepage: www.elsevier.com/locate/molcata
An efficient and reusable catalyst based on Pd/CeO for the room temperature
2
aerobic Suzuki–Miyaura reaction in water/ethanol
Francesco Amoroso , Sara Colussi , Alessandro Del Zotto , Jordi Llorca , Alessandro Trovarellia
a
a
a,∗
b
a
Dipartimento di Scienze e Tecnologie Chimiche, Università di Udine, via Cotonificio 108, 33100 Udine, Italy
Institut de Tècniques Energètiques, Universitat Politècnica de Catalunya, Diagonal 647, 08028 Barcelona, Spain
b
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 14 July 2009
Received in revised form
The Pd/CeO system behaves as an efficient precatalyst for the Suzuki–Miyaura cross-coupling under mild
conditions (298 K, in air) in ethanol/water. A broad range of aryl bromides, including those deactivated,
2
and arylboronic acids underwent Suzuki–Miyaura coupling with quantitative GC yields of asymmetric
biaryls. Isolated yields and purity of the coupling products were good to excellent. A careful investigation
through a series of suitable tests unequivocally showed that the C–C cross-coupling is accomplished via
homogeneous mechanism by leached palladium(0). Noticeably, the Pd/CeO2 system can be recycled at
least ten times without loss of activity.
1
7 September 2009
Accepted 18 September 2009
Available online 26 September 2009
Keywords:
©
2009 Elsevier B.V. All rights reserved.
Suzuki–Miyaura reaction
Cross-coupling
Palladium
Ceria
Biphenyls
1
. Introduction
For these practical and economical reasons, as well as for environ-
mental considerations, the use of simple heterogeneous catalysts
for the SM coupling is therefore highly desirable. In this context,
one of the fundamental aims is the production of fine chemicals
(especially pharmaceuticals) which must be free of residual metal
(<5 ppm).
The Suzuki–Miyaura (SM) reaction, based on the use of aryl-
boronic acids or esters, is recognized as one of the most important
synthetic methods for the construction of asymmetric biaryls
(
Scheme 1) [1–11]. It finds application in the production of agro-
chemical and pharmaceutical drugs and in material science. The
recent explosive growth of studies in this area is mainly due to air-
and moisture stability of organoboranes as well as to their low tox-
icity. Furthermore, the reaction tolerates a wide range of functional
groups and can be performed under relatively mild experimental
conditions. Usually, the SM coupling is homogeneously catalyzed
by palladium compounds generally in organic solvents or bipha-
sic systems. Recent investigations have confirmed the formation
of soluble colloidal nanoparticles which can act as the catalyst or,
more likely, as the precursor of the true catalyst [12–18]. Formation
of insoluble non-catalytic palladium black from small aggregates
is often observed as an undesired effect. The difficult removal of
the catalyst and its decomposition products from the mixture con-
taining the biaryl constitutes the main drawback of the reaction.
Furthermore, the ligands used for obtaining catalytically active
systems for the less reactive substrates are generally air- and/or
water-sensitive, expensive and often commercially not available.
While a variety of heterogeneous catalysts such as Pd/C,
Pd/zeolites, Pd/sepiolites, Pd/LDH, Pd/hydroxyapatites and Pd(II)
complexes anchored on different supports have been the subject
of several investigations [8–11], relatively few studies have been
focused on the use of palladium supported on metal oxides. To
the best of our knowledge, Pd-containing perovskites (in partic-
ular LaFe0.57Co0.38Pd0.05O ) [19,20], Pd/MgLa mixed oxides [21],
3
Pd/MgO [22], Pd/Al O3 [23,24], Pd/TiO2 [24–26], Pd/SiO2 [25], and
2
Pd-doped mixed oxides [27] are the only examples in this field
reported in the literature. Interestingly, Pd on various MO2 sup-
ports (M = Ti, Si, Zr and Ce) has shown to be catalytically active
for the homocoupling of phenylboronic acid [28]. Worth of note
is also the catalytic efficiency of supported gold (on Y O3 and
2
CeO ) for the same reaction [29,30]. The authors have also com-
2
pared isoelectronic Pd(II) and Au(III) supported on ceria finding
that the latter selectively promotes homocoupling, while the for-
mer catalyzes the cross-coupling reaction with lower activity and
selectivity [30]. In some cases palladium leaching during catalysis
was evidenced. Although no noble metal leaching was observed
using Pd/MgLa mixed oxides, in the first recycling the activity of
the catalytic system slightly decreased (after 1 h the yield dropped
∗ Corresponding author. Tel.: +39 432 558840; fax: +39 432 558803.
E-mail address: alessandro.delzotto@uniud.it (A. Del Zotto).
1
381-1169/$ – see front matter © 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.molcata.2009.09.012

1
98
F. Amoroso et al. / Journal of Molecular Catalysis A: Chemical 315 (2010) 197–204
Scheme 1. The Suzuki–Miyaura reaction (X = halogen).
Fig. 3. Particle size distribution relative to a fresh sample of Pd/CeO2.
Scheme 2. The model SM reaction between bromobenzene (1) and 4-tolylboronic
ꢀ
acid (2) leading to 4-methyl-1,1 -biphenyl (3).
of our knowledge, such a catalytic system has been previously
employed in two single experiments of Suzuki cross-coupling reac-
tion [24,30]. As a matter of fact, Pd/CeO2 showed less efficiency
with respect to Pd/Al2O3 and Pd/TiO2 systems [24]. On the con-
trary, the Pd/CeO2 system has found application in other catalytic
processes, for example CO, CO2, and hydrocarbons hydrogenations
Fig. 1. TEM micrograph of Pd/CeO2.
from 99 to 95%). No information was given by the authors on further
recycling of the catalyst [21]. The Pd-containing perovskite cata-
lyst was recycled four times without apparent loss of activity [19],
and a further detailed study revealed that the effective catalytic
species was present in solution-phase [20]. It is noteworthy that
Table 1
◦
◦
the catalytic runs have been performed at 60 C [8], 80 C [20,21]
Suzuki–Miyaura reaction of bromobenzene (1) with 4-tolylboronic acid (2) to yield
◦
ꢀ
a
and 150 C (under MW irradiation) [26]. Only in the case of the
4-methyl-1,1 -biphenyl (3) .
Pd/MgO catalyst the SM reaction was carried out at room tempera-
ture starting from aryl bromides and iodides [22]. Significantly, no
coupling product was formed at 25 C using Pd/MgLa mixed oxides
Entry
1
Catalyst
Pd/CeO2
Solvent (v/v ratio)
Base
Yield (%)b
>99%
Time (h)
11
◦
EGME/H2O
3:1
K2CO3
(
2 wt% Pd)
[
21].
With this scenario in mind, we initiated a study to evaluate
2
3
4
5
6
7
8
9
Pd/CeO2
Ethanol/H2O
3:1
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
KF
>99%
0%
8
(
2 wt% Pd)
the catalytic efficacy of Pd/CeO2 in the SM reaction. To the best
CeO2
Ethanol/H2O
12
3:1
Pd/CeO2
Ethanol/H2O
1:3
>99%
95%
40
(
2 wt% Pd)
Pd/CeO2
H2O
72
(
2 wt% Pd)
Pd/CeO2
Methanol/H2O
3:1
>99%
>99%
87%
8
(
2 wt% Pd)
Pd/CeO2
2-Propanol/H2O
3:1
30
(
2 wt% Pd)
Pd/CeO2
Ethanol/H2O
3:1
8
8
(
2 wt% Pd)
t
Pd/CeO2
Ethanol/H2O
3:1
KO Bu
92%
(
2 wt% Pd)
1
0
Pd/CeO2
(
Ethanol/H2O
3:1
K2CO3
K2CO3
>99%
>99%
16
2 wt% Pd)c
11
Pd/CeO2d
Ethanol/H2O
3:1
10 min
(
2 wt% Pd)
a
Reagents and conditions: 1 (0.5 mmol), 2 (0.6 mmol), base (0.6 mmol), catalyst
(
mol 1/mol Pd = 100), 2 mL solvent, and T = 298 K.
b
n
Determined by GC using diethylene glycol di butyl ether as internal standard.
1/Pd molar ratio = 1000.
c
Fig. 2. Representative HRTEM image of Pd/CeO2 along with Fourier transform (FT)
images.
d
At 353 K.

F. Amoroso et al. / Journal of Molecular Catalysis A: Chemical 315 (2010) 197–204
199
Table 2
a
Suzuki–Miyaura reaction between different aryl halides and arylboronic acids catalyzed by Pd/CeO2 .
Entry
1
Aryl halide
Arylboronic acid
Product
Yield (%)b
89
Time (h)c
3
8
14
10
2
3
4
5
4
86
87
85
95
5
6
1
1
7
6
7
8
83
88
3
9
4
7
8
9
10
88
91
11
1.5
1
0
12
85
96
a
b
c
Reaction conditions: aryl bromide (0.5 mmol), arylboronic acid (0.6 mmol), K2CO3 (0.6 mmol), Pd 1 mol%, ethanol 1.5 mL, H2O 0.5 mL, and T = 298 K.
Isolated yield. GC yields of all compounds 3–12, determined using diethylene glycol di butyl ether as internal standard, were >99%.
Necessary for quantitative formation of the product. Using Pd 0.1 mol%, compounds 3, 5 and 6 were obtained in >99% GC yield after 16, 48 and 3 h, respectively.
n
and C –C hydrogenolysis [31]. Herein we report the results of our
investigation which showed that Pd/CeO2 behaves as a very effi-
cient promoter of the SM reaction in a safety and benign solvent
samples gave 1.85 ± 0.04 wt%; however, for the sake of simplic-
2
6
ity, the nominal palladium percentage is reported throughout this
2
−1
paper. The B.E.T. surface area was 28 m g after calcination. The
X-ray diffraction analysis showed the presence of peaks belong-
ing to fluorite lattice of ceria but did not show distinct peaks
attributable to either PdO and Pd. To spread light into this fea-
ture, high-resolution transmission electron microscopy (HRTEM)
analysis of a freshly prepared sample was undertaken, and a gen-
eral view is shown in Fig. 1. The sample is dominated by particles
of CeO2 of ca. 20 nm in size. Fig. 2 (left) shows a representa-
tive HRTEM image of the sample along with Fourier transform
(FT) images of particles labeled a and b. Particle a exhibits lat-
tice fringes at 2.71 Å, which corresponds to (2 0 0) crystallographic
planes of CeO2. Particle b shows spots in the FT image at 3.05 Å,
which are ascribed to the (1 0 0) crystallographic planes of PdO.
PdO crystallites are well distributed over the CeO2 support, with a
particle size distribution centered at 6.7 nm (the particle size dis-
(
ethanol/water). Furthermore, this catalyst can be reused several
times (at least ten) without apparent loss of activity and such an
issue is crucial for scaling up this environmentally friendly catalytic
process.
2
. Results and discussion
2.1. Preparation and characterization of Pd/CeO2
The catalyst was prepared by the incipient wetness impreg-
nation method, followed by calcination at 1073 K, as previously
described for analogous compounds [32]. With respect to the
nominal 2 wt% Pd content, the elemental analysis of two distinct

2
00
F. Amoroso et al. / Journal of Molecular Catalysis A: Chemical 315 (2010) 197–204
tribution is shown in Fig. 3). In the sample prepared by Willis and
Guzman using a nanocrystalline ceria support, a larger range for
the particle size was observed (2–35 nm), which was centered at
about 15 nm [28]. Another representative image of this sample is
shown in Fig. 2 (right). Again, a PdO particle (labeled b) is sup-
ported over a CeO2 crystallite (particle a). The image shows an
atomically resolved CeO2 crystal oriented along the [1 1 0] crystal-
lographic direction, as deduced from the corresponding FT image.
In particle b, lattice fringes at 2.64 Å correspond to (1 0 1) crystal-
lographic planes of PdO. The HRTEM analysis of the sample did
not evidenced the presence of metallic palladium particles on the
ceria surface. On the other hand a portion of ca. 25% of total Pd
present in the sample did not cycle if exposed to O2 under tem-
perature programmed oxidation (TPO) conditions, which could
indicate the presence of Pd metal. Undetection of metallic Pd by
HRTEM could originate either from their dimensions which fall
outside the range of 2–100 nm and from the presence of Pd–PdO
core–shell particles when PdO particles are covered by thin Pd
metal shells.
Fig. 4. Pd/CeO2 recycling tests for the standard reaction between 1 and 2 to afford
. Reagents and conditions: 1 (0.5 mmol), 2 (0.6 mmol), K2CO3 (0.6 mmol), catalyst
mol 1/mol Pd = 100), ethanol 1.5 mL, H2O 0.5 mL, 298 K. Yield of 3 (based on 1) was
determined by GC after 9 h (298 K). The GC yields of 3 relative to the first use and
ten consecutive (grey columns) and parallel reuses (white columns) of the catalyst
are reported.
3
(
2
.2. Catalytic activity of Pd/CeO2 in the Suzuki–Miyaura reaction
test the limits of the catalytic system, also the formation of com-
pounds 5 and 6 starting from an electron rich and an electron poor
aryl bromide, respectively, was evaluated by using 0.1 mol% Pd.
Successfully, both biaryls were obtained again quantitatively.
Initially, the catalytic trials were run in EGME/H O (3:1, v/v)
2
(
EGME—ethylene glycol monomethyl ether), according to our pre-
vious studies that demonstrated the beneficial effect of this type of
solvent on the rate of Pd-catalyzed Heck [33,34] and Suzuki [35]
reactions. At 25 C, a complete conversion of bromobenzene (1)
and 4-tolylboronic acid (2) into 4-methyl-1,1 -biphenyl (3) (model
reaction, Scheme 2) was achieved in 11 h by using K CO3 as the
2.3. Catalyst reuse
◦
ꢀ
The reusability of the catalyst was examined in the case of
2
the model reaction (Scheme 2). Measurements were carried out
using a 1 mol% palladium amount for both consecutive and paral-
lel recycling (explicative details are given in Section 4). The results
have been summarized in Fig. 4, where yields of 3 relative to the
first use and ten successive reuses of the catalyst are reported. As
clearly evidenced by the histogram, the catalytic performance of
Pd/CeO2 did not appreciably fade after ten reuses. In particular,
the GC yield values found for the consecutive recycling were never
below 97%. Both sets of experiments were stopped after the tenth
reuse, but the lack of a neat decreasing trend may suggest that
Pd/CeO2 effectively behaves as an outstanding long-living catalyst,
and such a finding is of particular interest for its possible applica-
tion in large-scale syntheses of biaryls. As reported above, when
the reaction was performed at 353 K, complete formation of 3 was
achieved in about 12 min. At this temperature, the yield after the
base and 1 mol% amount of Pd with respect to 1 (Table 1, entry
1
). However, the reaction run in ethanol/H O (3:1, v/v) was faster,
2
as complete formation of 3 was obtained in 8 h (Table 1, entry
). The beneficial role played by ethanol in the SM reaction has
2
been already reported [36]. It is important to stress that, in the
same experimental conditions, no product was formed within 12 h
by employing palladium-free CeO2 (Table 1, entry 3). The use of
ethanol/H O in 1:3 (v/v) ratio or water alone, resulted in a neat
2
increase of the reaction time (Table 1, entries 4 and 5). Finally,
the reaction rate did not substantially change when ethanol was
replaced by methanol (Table 1, entry 6), while a very slow forma-
tion of 3 was observed by using 2-propanol/H O (3:1, v/v) (Table 1,
entry 7). On the light of these preliminary results, further catalytic
2
tests were run exclusively in ethanol/H O 3:1 (v/v). Other inorganic
bases have been screened, thus also KF and KO Bu have shown to be
2
t
effective. Though the reaction went to completion with both bases,
less than 92% of 3 was obtained after 8 h (Table 1, entries 8 and 9).
A neat decrease of catalyst amount apparently did not markedly
affect the reaction rate. For example, in the presence of 0.1 mol% of
Pd the yield of 3 after 8 h was 92%, while the complete conversion of
1
into 3 was achieved in 16 h (Table 1, entry 1). Finally, completion
of the model reaction was achieved within 10 min at 353 K (Table 1,
entry 11).
The results of a screening of different electron rich and elec-
tron poor aryl halides and arylboronic acids to give products 4–12,
which are collected in Table 2, successfully confirmed the efficiency
of Pd/CeO2 as promoter of the SM reaction and scope of the pro-
tocol. Compounds 4–11 were formed quantitatively after 1–14 h,
while the heterocycle 12 required about 4 days. All products were
isolated in the solid state in good to excellent yield and high purity
1
(
≥97% checked by H NMR). Purity was lower (93%) only in the
ꢀ
case of 4-methyl-1,1 -biphenyl (3), as it was contamined by 7%
,4 -dimethyl-1,1 -biphenyl (the byproduct arising from homocou-
ꢀ
ꢀ
4
pling of 2), which could not be separated by chromatography or
fractioned crystallization.
As reported above, the biaryl 3 can be quantitatively formed
even by lowering the catalyst amount to 0.1 mol% Pd. In order to
Fig. 5. Formation of product 3 as a function of time. Reaction conditions: 1
(
0.5 mmol), 2 (0.6 mmol), K2CO3 (0.6 mmol), Pd 1 mol%, ethanol 1.5 mL, H2O 0.5 mL,
T = 298 K.

F. Amoroso et al. / Journal of Molecular Catalysis A: Chemical 315 (2010) 197–204
201
Scheme 3. Palladium “trapping” by a diphosphane arm anchored to silica.
first two consecutive reuses was 98.9 and 99.1, thus apparently
the catalyst seems to maintain its stability even at high tempera-
ture.
2.4. Evidences for homogeneous catalysis
To possibly ascertain whether Pd/CeO2 operates by hetero-
geneous or homogeneous mechanism at room temperature, the
filtration test [37,38] and the CS2 test [38] were run on the model
reaction. The catalyst was filtered off from the reaction mixture
◦
after 15 min and the solution was then stirred at 25 C. The GC
measurement run immediately after filtration showed 19.8% yield
of 3, which increased to only 23.9% after 8 h, the time necessary
for completion of the reaction in the presence of Pd/CeO . Thus, a
2
drastic slowing down of the reaction rate was effectively achieved
upon elimination of the catalyst, but such a result did not provide
a decisive answer about the nature of the true active species. The
Fig. 6. TEM micrograph of a sample of Pd/CeO2 after four uses in catalysis.
CS2 test was accomplished by using three different CS /Pd molar
2
ratios, namely, 1:1, 1:10, and 1:50. In the first two cases product
3
was not detected in solution by GC within 24 h. Differently, the
0
.8 nm. When directly observed, the size of catalytically active col-
loidal nanoparticles were 1.7 nm (mean value) [14] or in the range
.1–2.6 nm [12]. On the other hand, the ICP-MS analysis showed
C–C coupling occurred when the CS /Pd molar ratio was 1:50 at
2
roughly the same rate as that observed in the absence of carbon
sulfide. Such a result is generally considered as proof of occurrence
of heterogeneous mechanism, although it should not be viewed as
conclusive [7,20,38]. On the contrary, enlightening was the result
of a third test, which was performed by introducing in the reaction
mixture a Davisil silica with a 150 Å mean pore size functionalized
with a bis(diphenylphosphane) bidentate ligand [39], (Scheme 3).
Such a kind of poisoning test was first adopted in the Heck C–C
coupling by Jones and co-workers [40] and then applied by Richard-
son and Jones to both Heck [41,42] and SM [42] reactions. Thus, in
1
that 1.4 ppb (instrumental detection limit: 0.5 ppb) of palladium
was present, at the end of the reaction, in the filtered solution after
the first use of the catalyst. Thus, though in very low concentra-
tion, palladium is effectively present in solution as result of metal
leaching from the solid precatalyst. These results seem to suggest
that Pd/CeO acts as a reservoir of “homeopathic” amounts [48–50]
2
of catalytically active palladium. Furthermore, the maintenance of
catalytic activity upon several reuses could be reasonably explained
by a release/re-deposition mechanism [46,51–54], the latter being
favoured by the low temperature at which the catalytic process
is carried out [54]. Our finding is in line with the results reported
by Köhler et al. who nicely demonstrated the presence of higher
concentration of noble metal during SM catalysis with respect to
that measured when the reagents are almost consumed [24]. In our
the presence of a twice molar amount of the –N(CH PPh ) func-
tionality with respect to total palladium present in the reaction
vessel, the catalytic activity was nearly suppressed, as only 2.8% of
2
2 2
3
was formed after 8 h. The amount of added silica was based on
−
1
the loading of organic functionality (0.39 mmol g ) obtained by
combination between elemental analysis (N, P) and TGA measure-
ments [39]. Therefore, the diphosphane arm is able to extinguish
catalysis by chelating a soluble form of palladium, which acts as
the effective catalyst. Some authors have suggested that the true
catalyst should be a mononuclear Pd(0) species generated by solu-
ble colloidal nanoparticles, which in turn arise from the precatalyst
[
12–18,43]. As only traces of noble metal are effectively present in
solution at a ppb level (see below), there is indeed a large excess
of supported poisoning bidentate ligand. Notably, Richarson and
Jones have found that 35 equiv. of PVPy poison are ineffective,
while catalysis was almost stopped in the presence of 350 equiv.
of the same polymer [42]. In line with the hypothesis of forma-
tion of an active soluble species from supported palladium, the
kinetic plot (Fig. 5) shows the typical sigmoidal shape associated
with an induction period of the reaction due to formation of the
true catalyst in C–C coupling reactions starting from aryl halides
[
40–47]. It is quite evident, however, that its generation takes
place very rapidly. To check the presence of any nanometric pal-
ladium species in solution, after the third reuse of the catalyst, the
mother liquor was carefully analyzed by HRTEM, but no evidence
for the presence of metal nanoparticles was found. The detec-
tion limit of Pd entities under the conditions employed is about
Fig. 7. Comparison of particle size distribution between a fresh sample of Pd/CeO2
(
squares) and a sample used four times as catalyst of the standard reaction (trian-
gles).

2
02
F. Amoroso et al. / Journal of Molecular Catalysis A: Chemical 315 (2010) 197–204
Fig. 8. Representative HRTEM image of a sample of Pd/CeO2 after four uses in catalysis along with Fourier transform (FT) images.
vent (residual CHCl at 7.26 ppm for 1H and CDCl3 at 77.0 ppm
case, the results of the HRTEM analysis of a catalyst sample used
four times show that it is virtually indistinguishable from the fresh
material. Fig. 6 corresponds to a low magnification image of the
recycled sample, where the distribution and appearance of CeO2
support particles are similar to those of the freshly prepared cata-
lyst (Fig. 1). The HRTEM study of the used sample also denotes the
presence of PdO crystallites, and the particle size distribution is only
slightly biased towards larger particles (Fig. 7). The mean particle
size has increased only from 6.7 to 6.9 nm. Fig. 8 shows a represen-
tative HRTEM picture of the used sample, where two PdO particles
have been identified. The FT image recorded over the selected area
shows spots at 2.64 Å, which are ascribed to the (1 0 1) crystallo-
graphic planes of PdO. A second representative HRTEM image is
depicted in the same figure. Again, spots at 2.64 Å are recognized
in the FT image of the area selected, in accordance to PdO (1 0 1)
crystallographic planes.
3
13
for C). The high-resolution transmission electron microscopy
(HRTEM) was carried out at 200 kV with a JEOL 2010F instrument
equipped with a field emission gun. The point-to-point resolu-
tion of the microscope was 0.19 nm and the resolution between
lines was 0.14 nm. The powder samples were directly deposited
on holey-carbon coated Cu grids, whereas a drop of the mother
liquor was deposited and evaporated on a grid covered by a thin
polymer. The Pd loading of the catalyst was measured in the Micro-
analytical Laboratory of the Department of Chemical Sciences and
Technologies (Udine) on a Spectro Analytical Instruments Spec-
tromass 2000 Type MSDIA10B Inductively Coupled Plasma Mass
spectrometer. Samples (20 mg) were digested on a microwave
apparatus MILESTONE Mega 1200 by use of 1 mL of 65% HNO3,
0.4 mL of 30% H O2 and 0.1 mL of 40% HF with a mineralization
2
program at 650 W for 20 min in Teflon vessels. The mean value
for two different samples was 1.85 ± 0.04%. For the Pd determina-
tion in solution, four different samples were prepared by filtration
and centrifugation (1 min at 4000 rpm) of the reaction mixture
obtained after a catalytic complete conversion of 1 into 3. Each
sample was digested as described above on a microwave appa-
ratus MILESTONE Mega 1200. The mean concentration value of
Pd was 1.4 ppb (instrumental detection limit: 0.5 ppb). Calibration
curves were obtained by using a Palladium ICP/DCP standard solu-
tion purchased from Aldrich (10,000 mg/mL Pd in 6% HCl solution).
The GC–MS analyses, run to control the identity of the compounds
obtained in the catalytic trials, were carried out with a Fisons TRIO
2000 gaschromatograph–mass spectrometer working in the pos-
itive ion 70 eV electron impact mode. Injector temperature was
3
. Conclusions
We have shown that Pd/CeO2 behaves as an efficient catalyst in
the SM coupling reaction starting from aryl bromides with different
electronic substituents. The most remarkable results of the present
investigation are the following: (i) the catalyst is active at room
temperature, in air, in an environmentally friendly solvent such as
3
:1 ethanol/water mixture; (ii) Pd/CeO2 can be easily prepared, is
relatively cheap and is active also in low amount (Pd 0.1 mol%);
iii) all couples of substrates employed were quantitatively trans-
(
formed into the coupling product; (iv) the catalyst can be recycled
at least ten times without appreciable decrease of activity. For all
◦
®
these reasons, the Pd/CeO system seems to be a good candidate for
kept at 250 C and the column (Supelco SE-54, 30 m long, 0.25 mm
2
large-scale applications of the SM reaction. We have also demon-
strated that a homogeneous mechanism takes place most probably
through a release/re-deposition process. At the end of the reaction
the amount of palladium in solution was at the ppb level. Thus, if
the coupling product showed comparable metal content, it is clear
that our procedure meets the requirements of the pharmaceutical
industry (<5 ppm residual metal in the commercial product).
i.d., coated with a 0.5 ␮m phenyl methyl silicone film) temperature
◦
◦
was programmed from 60 to 300 C with a gradient of 10 C/min.
The GC analyses were run on a Fisons GC 8000 Series gaschro-
matograph equipped with a Supelco® PTA-5 column (30 m long,
0.53 mm i.d., coated with a 3.0 ␮m poly(5% diphenyl–95% dimethyl-
siloxane) film) Injector and column temperatures as indicated
above.
4
. Experimental
4.2. Catalyst preparation and characterization
4
.1. General
The catalyst was prepared by incipient wetness on a com-
mercial CeO2 support (B.E.T. surface area after calcination at
2
−1
All reagents were purchased from Aldrich and used without
1073 K = 31 m g ). The Pd precursor was a 10% Pd(NO3)2 solu-
tion (99.999%), which was added to the support drop by drop
to obtain a catalyst with a nominal Pd loading of 2 wt%. After
impregnation the powder was dried overnight at 393 K and then
further purification. Commercial solvents were dried according
1
to standard methods and freshly distilled before use. The H and
13
1
C{ H} NMR spectra (at 200.13 and 50.32 MHz, respectively) have
2
−1
been recorded on a Bruker AC 200 F QNP spectrometer. For both
nuclei the chemical shifts were referenced to the signal of the sol-
calcined at 1073 K for 2 h. B.E.T. surface area was 28 m g after
calcination. The X-ray spectra were recorded on a Philips X’Pert

F. Amoroso et al. / Journal of Molecular Catalysis A: Chemical 315 (2010) 197–204
203
m), 7.73–7.41 (6H, m); 13C NMR (CDCl ) ı 147.4, 147.1, 137.7, 133.7,
diffractometer equipped with Cu K-alpha radiation source. Step
size was 0.01 with a time-per-step of 80 s. The temperature pro-
grammed oxidation (TPO) experiment was carried out on 150 mg
3
◦
130.8, 128.9, 128.5, 127.0, 126.7, 126.2, 125.3, 125.1.
1
5-Phenylpyrimidine 12. Yield, 85%; purity, 97%; H NMR (CDCl )
3
ı 9.19 (1H, s), 8.93 (2H, s), 7.61–7.43 (5H, m); 13C NMR (CDCl ) ı
of Pd/CeO . The catalyst was exposed to a flow of 2% of oxy-
2
3
gen in nitrogen, while the temperature was increased from room
temperature up to 1273 K and then decreased to 373 K for two
subsequent heating/cooling cycles at 10 C/min. Oxygen release
during heating (due to PdO decomposition) and oxygen uptake
during cooling (due to Pd reoxidation) were measured. Quanti-
tative analysis of the oxygen release/uptake allowed to evaluate
the amount of Pd in oxide form (75%) present on the catalyst
surface.
157.4, 154.8, 134.3, 134.2, 129.3, 128.9, 126.8.
◦
4.4. Catalytic runs
The following procedure was adopted for the standard reac-
tion catalyzed by Pd/CeO2 (1 mol% Pd). In a thermostatted bath
◦
at 25 C, a 10 mL Schlenk flask was charged in air with a mag-
netic stir bar, Pd/CeO2 (Pd 2 wt%) (26.6 mg), 4-tolylboronic acid (2)
n
(
0.6 mmol), diethylene glycol di butyl ether (GC internal standard,
4.3. Synthesis and NMR characterization of biaryls 3–12
0
.5 mmol), K CO3 (0.6 mmol), ethanol (1.5 mL) and H O (0.5 mL).
2
2
Then the reaction was started by addition of bromobenzene (1)
0.5 mmol). The mixture was extracted from the flask by means
◦
In a thermostatted bath at 25 C, a 25 mL Schlenk flask was
(
charged in air with a magnetic stir bar, Pd/CeO2 (Pd 2 wt%)
53.2 mg), the appropriate arylboronic acid (1.2 mmol) and aryl
bromide (1.0 mmol), K CO3 (1.2 mmol), ethanol (3.0 mL) and H O
of a syringe (the volume of the sample was ca. 0.1 mL). To the
sample was added 0.5 mL of water, followed by immediate extrac-
tion with dichloromethane (2× 1 mL). The solution was dried
over Na SO and analyzed by GC after purification on a micro-
(
2
2
(
1.0 mL). The reaction mixture was kept under vigorous stirring
2
4
until the GC control showed no residual aryl bromide in solution.
Water (10 mL) was added to the suspension and the organics were
extracted with dichloromethane (3× 10 mL). The organic phase was
dried over Na SO and then passed through a column filled with
column filled with silica gel. All other catalytic trials were carried
out similarly, using Celite® instead of silica gel in the case of
product 12.
2
4
®
silica gel (3–11) or Celite (12). Elimination of the solvent under
vacuum gave the desired biaryl as white microcrystalline solid.
Purity was checked by H NMR.
4.5. Catalyst recycling
1
1
13
1
H and C{ H} NMR data (spin multiplicity is given by s: singlet,
Two different methods for catalyst recycling were employed:
(a) consecutive reuse, (b) parallel reuse. Method (a): in a ther-
mostatted bath at 25 C, a 8 mL conical centrifuge test tube was
q: quartet, st: septet, m: multiplet, dt: doublet of triplets, and ddt:
doublet of doublets of triplets):
◦
ꢀ
ꢀ
4
-Methyl-1,1 -biphenyl 3. Yield, 89%; purity, 93% (7% 4,4 -
charged in air with a magnetic stir bar, Pd/CeO2 (2 wt% Pd)
1
dimethylbiphenyl); H NMR (CDCl ) ı 7.73–7.26 (9H, m), 2.47 (3H,
(26.6 mg), 4-tolylboronic acid (2) (0.6 mmol), diethylene glycol
3
13
n
s); C NMR (CDCl ) ı 141.1, 138.3, 137.0, 135.7, 129.5, 128.7, 127.0,
di butyl ether (GC internal standard, 0.5 mmol), K2CO3 (0.6 mmol),
3
1
26.9, 21.1 (CH ).
ethanol (1.5 mL) and H2O (0.5 mL), and the reaction was started
upon addition of bromobenzene (1) (0.5 mmol). After 9 h, the sus-
pension was centrifuged for 3 min at 3500 rpm and the supernatant
was removed and analyzed by GC. The solid was washed with
water and ethanol, dried on air and reused for the second test,
which was performed upon addition in sequence of solvents, 2,
GC internal standard, base and 1, as indicated above. Again, the
reaction was stopped after 9 h by centrifugation and the successive
workup was analogous to that previously described. Iteration of
this procedure was continued for other nine reuses of the catalyst.
The yields of 3 from the GC measurements were the following:
99.9 (first use), 99.9, 99.6, 98.4, 98.4, 97.8, 97.0, 98.7, 97.9, 97.0,
97.6. Method (b): a 50 mL Schlenk flask was charged with a mag-
netic stir bar, Pd/CeO2 (2 wt% Pd) (400 mg), 4-tolylboronic acid (2)
(9 mmol), K2CO3 (9 mmol), ethanol (22.5 mL) and H2O (7.5 mL),
and the reaction was started upon addition of bromobenzene (1)
(7.5 mmol). The reaction was stopped when 1 was quantitatively
converted into product 3, as judged by GC. The solid was then
recovered by filtration, washed with water and ethanol and dried
under vacuum. A sample of 26.6 mg was used for the first recy-
cling test (amounts of organic substrates, GC internal standard,
base and solvents were as indicated above for method (a)), the
reaction was stopped after 9 h and the solution was analyzed by
GC. The remaining amount of catalyst, after weighting, was used to
convert completely 1 into 3 by employing appropriate amounts of
organic substrates, base, GC internal standard and solvents. Again,
a sample of 26.6 mg was used for the second recycling test which
was stopped after 9 h, while all the remaining catalyst was used
for the catalytic transformation of 1 and 2 into 3. This proce-
dure was then iterated for a total of ten reuses of the catalyst.
The yields of 3 from the GC measurements were the following:
99.9 (first use), 99.2, 99.4, 99.5, 99.8, 99.3, 99.1, 99.4, 99.2, 99.0,
98.6.
3
ꢀ
1
4
-Methoxy-1,1 -biphenyl 4. Yield, 86%; purity, 98%; H NMR
1
3
(
CDCl ) ı 7.63–7.28 (7H, m), 7.06–6.96 (2H, m), 3.88 (3H, s);
C
3
NMR (CDCl ) ı 159.1, 140.8, 133.7, 128.7, 128.1, 126.7, 126.6, 114.2,
3
5
5.3 (OCH ).
3
ꢀ
ꢀ
4
-Methoxy-4 -methyl-1,1 -biphenyl 5. Yield, 87%; purity, 98%;
1
H NMR (CDCl ) ı 7.64–7.48 (4H, m), 7.36–7.25 (2H, m), 7.09–7.00
3
13
(
2H, m) 3.90 (3H, s), 2.47 (3H, s); C NMR (CDCl ) ı 158.9, 137.9,
3
1
36.3, 133.7, 129.4, 127.9, 126.5, 114.1, 55.2 (OCH ), 21.0 (CH ).
3 3
-Methyl-4 -nitro-1,1 -biphenyl 6. Yield, 85%; purity, 98%; 1H
ꢀ
ꢀ
4
NMR (CDCl ) ı 8.32–8.23 (2H, m), 7.76–7.67 (2H, m), 7.58–7.49
3
1
3
(
2H, m), 7.36–7.27 (2H, m), 2.44 (3H, s); C NMR (CDCl ) ı 147.5,
3
1
46.7, 139.0, 135.7, 129.8, 127.4, 127.1, 124.0, 21.1 (CH ).
3
ꢀ
ꢀ
4
-Cyano-4 -methoxy-1,1 -biphenyl 7. Yield, 95%; purity, 99%;
1
H NMR (CDCl ) ı 7.73–7.48 (6H, m), 7.04–6.95 (2H, m), 3.86 (3H,
3
13
s); C NMR (CDCl ) ı 160.1, 145.1, 137.0, 132.5, 132.4, 131.4, 128.3,
1
3
27.0, 110.0 (CN), 55.3 (OCH ).
3
ꢀ
ꢀ
1
4
-Cyano-3-ethanoyl-1,1 -biphenyl 8. Yield, 83%; purity, 99%; H
NMR (CDCl ) ı 8.18 (1H, dt), 7.99 (1H, ddt), 7.82–7.66 (5H, m), 7.59
3
1
3
(
1H, dt), 2.66 (3H, s); C NMR (CDCl ) ı 197.6 (C O), 144.5, 139.6,
3
1
2
37.8, 132.6, 131.6, 129.4, 128.5, 127.8, 126.8, 118.6, 111.4 (CN),
6.8 (CH ).
3
ꢀ
ꢀ
3
,5-Di(trifluoromethyl)-4 -nitro-1,1 -biphenyl 9. Yield, 88%;
1
purity, 98%; H NMR (CDCl ) ı 8.43–8.21 (2H, m), 8.11–7.91 (3H,
3
m), 7.87–7.74 (2H, m); 13C NMR (CDCl ) ı 148.1, 144.3, 141.0,
3
1
32.7 (q, JCF = 33.6 Hz), 128.3, 127.5 (q, JCF = 4.7 Hz), 124.5, 123.1 (q,
JCF = 272.2 Hz, CF ), 122.5 (st, J = 4.3 Hz).
3
CF
ꢀ
ꢀ
4
-Chloro-4 -methoxy-1,1 -biphenyl 10. Yield, 88%; purity, 99%;
1
H NMR (CDCl ) ı 7.55–7.45 (4H, m), 7.43–7.34 (2H, m), 7.04–6.94
3
1
3
(
2H, m), 3.86 (3H, s); C NMR (CDCl ) ı 159.3, 139.2, 132.6, 132.4,
3
1
28.8, 127.9, 114.3, 55.3 (CH ).
1
3
-(4-Nitrophenyl)naphthalene 11. Yield, 91%; purity, 98%; 1H
NMR (CDCl ) ı 8.40–8.31 (2H, m) 8.01–7.91 (2H, m), 7.84–7.77 (1H,
3

2
04
F. Amoroso et al. / Journal of Molecular Catalysis A: Chemical 315 (2010) 197–204
[26] L.-S. Zhong, J.-S. Hu, Z.-M. Cui, L.-J. Wan, W.-G. Song, Chem. Mater. 19 (2007)
Acknowledgement
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[
27] U. Kazmaier, S. Hähn, T.D. Weiss, R. Kautenburger, W.F. Maier, Synlett (2007)
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measurements.
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